It is well known that the activity of calcineurin (CaN) could be modulated by several transitional metal ions. In the present work, the effects of a calcium analog, lanthanum ion (La(3+)), on the activity of CaN were studied. It was found that La(3+) exerted multiple effects on CaN activity. La(3+) could stimulate CaN in the absence of calmodulin (CaM); whereas at low concentrations of La(3+), there was a slight inhibition of activation of CaN in the presence of CaM. Competitive experiments and limited trypsin proteolysis confirmed that La(3+) did not act on the catalytic core of CaN, but exerted its effect through direct action on the CaN regulatory domain similar to Mg(2+). In activity titration and spot blotting studies, La(3+)-containing CaM complexes were less effective in stimulating CaN than Ca(2+) or Mn(2+)-containing CaM; however, the binding affinity of these metal-CaM complexes to CaN was similar. These effects of La(3+) on CaN activity are unique among metal ions and may provide clues to understand the biological effects of La(3+).